Between 10-30% of patients with symptoms similar to angina and sufficient to justify cardiac catheterization are often found to have normal coronary angiograms. Since coronary artery disease (the typical organic cause of chest pain) is not the cause of the chest pain, management of chest pain patients with no apparent cardiac etiology is a major clinical problem.
Most of these patients continue to experience chest pain, often resulting in visits to the emergency room and occasionally even repeat cardiac catheterization. See, for instance, Papanicolaou et al., "Prognostic Implications of Angiographically Normal and Insignificantly Narrowed Coronary Arteries", Am. J. Cardiol., 58(13): 1181-1187 (Dec. 1, 1986); Proudfit et al., "Selective Cine Coronary Arteriography. Correlation with Clinical Findings in 1,000 Patients", Circulation, 33(6): 901-910 (June, 1966); Dart et al., "Angina' and Normal Coronary Arteriograms: A Follow-up Study", Eur. Heart J., 1(2): 97-100 (1980); Dart et al., "Chest Pain with Normal Coronary Arteries", Lancet, 1(8163): 311 (Feb. 9, 1980); Kemp et al., "The Anginal Syndrome Associated with Normal Coronary Arteriograms. Report of a Six Year Experience", Am. J. Med., 54(6): 735-742 (June, 1973); Kemp et al., "Seven Year Survival of Patients with Normal or Near Normal Coronary Arteriograms: A CASS Registry Study", J. Am. Coll. Cardiol. 7(3): 479-483 (March, 1986.); and Cannon, R. O. 3.sup.rd, "The Conundrum of Cardiovascular Syndrome X", Cardiol. in Rev., 6(4): 213-220 (1998).
Thus, the condition of non-cardiac chest pain has considerable effects on quality of life and utilization of health care resources, resulting from a poor symptomatic, functional, and psychological outcome. Although most patients with non-cardiac chest pain are discharged after being reassured, they rarely feel reassured and often desire additional clinical evaluations. The basis of unexplained chest pain and the management of patients who have unexplained chest pain, despite a normal coronary angiogram and/or a normal stress test, is controversial. They continue to believe that they have significant disease which has been missed. See, for instance, Lantinga et al., "One-year Psychosocial Follow-up of Patients with Chest Pain and Angiographically Normal Coronary Arteries", American Journal of Cardiology, 62 (4): 209-213, (Aug. 1, 1988); Potts et al., "Psychosocial Outcome and Use of Medical Resources in Patients with Chest Pain and Normal or Near-normal Coronary Arteries: A Long-term Follow-up Study", Q. Journal of Medicine, 86 (9): 583-593 (1993); Mayou et al., "Management of Non-cardiac Pain: from Research to Clinical Practice", Heart, 81(4): 387-392 (1999); Cannon, R. O. 3.sup.rd, "Can Measures of Coronary Dynamics Explain Chest Pain without Coronary Artery Disease?", Mayo Clinic Proceedings, 73 (12): 1226-1228 (December, 1998); Cannon, R. O. 3.sup.rd ; "Does Coronary Endothelial Dysfunction Cause Myocardial lschemia in the Absence of Obstructive Coronary Artery Disease?", Circulation, 96(10): 3251-3254 (Nov. 18, 1997); Richter et al., "Chest Pain with Normal Coronary Arteries. Another Perspective", Digestive Diseases and Sciences, 35(12): 1441-1444 (December, 1990); Cannon, R. O. 3.sup.rd ; "How to Manage Chest Pain in Patients with Normal Coronary Angiograms", Cardiologia, 42 (1): 21-29, (January, 1997); and Cannon, R. O. 3.sup.rd ; "Chest Pain and the Sensitive Heart", Eur. J. of Gastroenterol. & Hegatol., 7(12): 1166-1171 (1995).
Estimates are that a person with chest pain that is non-cardiac (because the coronary angiogram was normal) spends about $3,500 a year to manage this pain. See, for instance, Richter et al., "Esophageal Chest Pain: Current Controversies in Pathogenesis, Diagnosis, and Therapy", Annals of Internal Med., 110(1): 66-78 (Jan. 1, 1989). Furthermore, although coronary artery disease is ruled out to be the cause of the chest pain (since the coronary angiogram was normal), other medical causes exist, which can be the cause of the chest pain.
For instance, other medical causes of non-cardiac chest pain may be organic. Examples of organic causes include Prinzmetal angina, microvascular angina and potentially esophageal, rheumatological and pulmonary diseases. See, for instance, Chambers, "Chest Pain: Heart, Body or Mind?", Journal of Psychosomatic Research, 43(2): 161-167 (1997); and Jolobe et al., "Comparative Study of Chest Pain Characteristics in Patients with Normal and Abnormal Coronary Angiograms", Heart, 80(2): 210 (1998). However, frequently no organic cause can be found.
Also, other medical causes of non-cardiac chest pain may be psychiatric. More particularly, psychiatric evaluation of these patients with non-cardiac chest pain has suggested that a significant proportion of them may meet the criteria for panic disorder. Depressive symptoms may also occur in these patients. Many other patients also have some symptoms of anxiety, though these patients do not meet clinical diagnostic criteria for panic disorder and/or other psychiatric disorders. See, for instance, Katon et al., "Chest Pain: Relationship of Psychiatric Illness to Coronary Arteriographic Results", The American Journal of Medicine, 84(1): 1-9 (January 1988); and Cannon, R. O. 3.sup.rd, et al, "Imipramine in Patients with Chest Pain Despite Normal Coronary Angiograms", The New England Journal of Medicine, 330 (20): 1411-1417 (May 19, 1994).
An early randomized, double-blind, placebo-controlled study that used a psychotropic drug to evaluate the treatment of chest pain, despite normal coronary angiograms, was reported by Cannon et al. in "Imipramine in Patients . . . " supra. In this study, 60 patients, some with and some without psychiatric disorders, underwent treatment in a double-blind protocol receiving clonidine 0.1 mg (twice a day), imipramine (50 mg nightly), or placebo (twice a day). (Clondine is an antihypertensive, and imipramine is a tricyclic antidepressant and a member of the dibenzazepine group.) Patients were treated initially with a single blind placebo, given twice a day, and pain ratings were evaluated using a simple scale based on a daily pain diary. The patients were then randomized to either drug or placebo. The reduction in the frequency of chest pain in the imipramine group was approximately 50% compared to the placebo group. This benefit was seen irrespective of either current or past psychiatric disease. The effect was noted within 3 weeks. Also noted was a reduction in right ventricle sensitivity to pain.
The benefit of imipramine in the treatment of non-cardiac chest pain has been recently confirmed. See, for instance, Cox et al., "Low Dose lmipramine Improves Chest Pain but not Quality of Life in Patients with Angina and Normal Coronary Angiograms", Eur. Heart J., 19(2):250-254 (February, 1998).
In another study reported by Cannon, R. O. 3.sup.rd, in "Does Coronary Endothelial Dysfunction . . . " supra is a suggestion that microvascular dysfunction may cause myocardial ischemia during stress in a subset of patients, particularly those who have abnormal stress tests, even through they have normal coronary angiograms. Additional studies reported by Cannon, R. O. 3.sup.rd, and one study reported by Quyyumi et al. suggest patients with chest pain, normal coronary angiograms, and ischemic appearing exercise electrocardiograms may have exaggerated or abnormal cardiac pain perception. See, for instance, Cannon, R. O. 3.sup.rd, "The Sensitive Heart. A Syndrome of Abnormal Cardiac Pain Perception", JAMA, 273(11): 883-887 (Mar. 15, 1995); Cannon, R. O. 3.sup.rd, "Chest Pain with Normal Coronary Angiograms", N. Engl. J. Med., 328(23): 1706-1708 (Jun. 10, 1993); Cannon, R. O. .sub.3.sup.rd, "Chest Pain as a Consequence of Abnormal Visceral Nociception", Dig. Dis. and Sci., 38(2): 193-196 (February, 1993); Quyyumi et al., "Endothelial Dysfunction in Patients with Chest Pain and Normal Coronary Arteries", Circulation, 86(6): 1864-1871 (December, 1992); Holdright, "Chest Pain with Normal Coronary Arteries", Br. J. Hosp. Med., 56(7): 347-350 (1996); and Cannon, R. O. 3.sup.rd, "Causes of Chest Pain in Patients with Normal Coronary Angiograms: The Eye of the Beholder", The American Journal of Cardiology, 62: 306-308 (Aug. 1, 1988).
A medicament beneficial in treating patients with non-cardiac chest pain is clearly still needed. Also, a medicament beneficial in ameliorating the symptoms of GERD in patients with GERD is clearly still needed. Surprisingly, the present inventors have found that SSRIs are of benefit to these patients.